JP2009507807A - Novel use of a composition having chloroprocaine hydrochloride, novel composition having chloroprocaine hydrochloride, and method for producing - Google Patents

Abstract

  The present invention relates to a novel use for compositions having chloroprocaine hydrochloride, and in particular to the use in the manufacture of drugs for intrathecal anesthesia. The present invention also relates to a new composition having chloroprocaine hydrochloride particularly suitable for this new use, and to a new process for making this composition.

Description

  The present invention relates to the field of intrathecal anesthesia and provides a novel composition suitable for a particular form of administration.

  According to the requirements of private insurance companies that constrain national health services and medical costs to perform the most possible number of surgical operations without general anesthesia and thus without hospitalizing patients Given the current trends in affected medicines, there is currently an interest in further developing peripheral and local anesthesia over common anesthesia techniques. Given the current developments and significant progress achieved, local and peripheral anesthesia has proven to be safer than general anesthesia and is therefore avoided especially in vulnerable patients such as the elderly. Is. Therefore, it is a problem not only at the expense to be borne by the community, but also at improving all the quality of treatment imposed on the patient, improving compliance.

  The so-called local anesthesia generally includes techniques suitable for local anesthesia to the spinal column and upper limb plexus and to local anesthesia to individual peripheral nerves. Spinal anesthesia techniques are categorized in turn as epidural and intrathecal injection, whereby the anesthetic is injected into the so-called subarachnoid space, both of which are targeted anesthetic injections into the spinal cavity Is suitable for inducing local anesthesia of the lower limbs by temporarily blocking the neural connection between the limbs and the brain. While intrathecal techniques are more invasive than epidural techniques (injecting deeper into the spinal cord), they have the advantage of using a relatively small amount of anesthetic.

  Intrathecal anesthesia, ideal for surgical use in outpatients, should have immediate or at least rapid effects (thus having a very short induction period, the so-called onset time) and predictable It should have a more easily tunable effect over a period of time and should exhibit low neurotoxicity without side effects.

An anesthetic already used for intrathecal anesthesia is procaine, which can lead to an inadequacy rate of 17% (1). Instead, lidocaine is associated with various syndromes of the so-called Transient Neurological Syndrome (TNS) (Non-Patent Document 2), and in terms of efficacy, bupivacaine is nevertheless low dose However, in some cases, blockage can be induced that is difficult to predict duration.
Hodgson, PS. Liu SS. , Batra MS. Et al., “Procaine compared with lidocaine for incident of transient neurological symbols”, Reg. Anesth. Pain Med. 2000, 25, p. 218-22 Pollock JE. “Transient neurological symptoms: etiology, risk factors, and managements”, Reg. Anesth. Pain Med. 2002, 27, p. 581-6 Niesel HCH. "Regional ashesie Localathesia Reginale Scherztherapie", G. Thime Verlag, Stuttgart, 1994, p. 83-86 Prithvi Raj P.M. "Practical Management of Pain", Mosby, St. Louis (3), 2000, p. 557-572 Covino BG. And Vassallo HG. "Local anthetics: Mechanisms of Action and Clinical Use", Grune & Stratton, N .; York, 1976, p. 114-115 Covino BG. "Pharmacology of local anesthetic agents", Br. J. et al. Anaesth, 1986, 58, p. 701-716 Folders FF. And McNaII PG. "2-Chloroprocane: a new local anesthetic agent", Anestheology, 1952, vol. 13, p. 287-96 Winnie AP. Nader AM. "Santayana's property fullfilled", Reg. Anesth. Pain Med. 2001, vol. 26, p. 558-64 Wang BC. Hillmann DE. Spielhoz NI. "Chronic neurological deci- tects and Nescaine-CE an effect of the anesthetic, 2-chloropro- cine, or the antioxidant, sodium bisulfite?" 1984, 63, p. 445-7 Gissen AJ. Datta S .; Lambert D .; Author, “The chloroprone control”, Reg. anesth. 1984, Vol. 9, p. 124-45 Wang BC. Li D .; Hiller JM. , “Lumbar subbarachnoid ethylene tetraacetate inducements Hind lign te n ban ent e s ren e s e n e s s s s ation” ”,“ prevention by CaCl2 pretension ”; 1992, 75, p. 895-899 Vath JS. And Kopacz DJ. Author, “Spinal 2-chloroprosine: the effect of added fentanyl”, Anesth. Analg. 2004, Vol. 98, p. 81-88 Palas TAR. Authors, “Two years experience with 1% chloroprobe for spinal anesthesia, in the anesthesia,” Society for the University, 29 et al. Kouri ME. And Kopacz DJ. "Spinal 2-chloroprosine: a comparison with lidocaine in volunters", Anesth Analg. 2004, Vol. 98, p. 75-80 Warren DT. And Kopacz DJ. "Spinal 2-chloropro- teine: the effect of added depth", Anesth Analg. 2004, Vol. 98, p. 95-101 Taniguchi M. Boyen AW. And Drsner K. et al. "Sodium bisulfite. Scapegoat for chloroprone neurotoxicity?", Anestheology, 2004, 100, p. 85-91 Drsner, Kenneth, “Chloropine Spinal Anesthesia: Back to the Future?”, Anesth. Analg. 2005, 100, p. 549-52

  Thus, none of the anesthesia in the currently officially used prescription used to be applied intrathecally appears to completely meet all the criteria that characterize an ideal preparation. Accordingly, there is a need to provide additional and improved compositions for intrathecal administration.

  In an attempt to solve the above-mentioned problems, the inventors of the present application have found that the above-mentioned problems in the prior art have an aqueous solution of chloroprocaine hydrochloride and no preservatives for the manufacture of drugs for intrathecal anesthesia. It has surprisingly been found to be solved using an injectable composition.

  The present inventors have also found a method for producing a drug useful for intrathecal anesthesia, which is characterized by using a composition having an aqueous solution of chloroprocaine hydrochloride and no preservative for injection. To do. Furthermore, the inventors have found a novel pharmaceutical composition in the form of an aqueous solution, which is particularly suitable for intrathecal administration and consists of the following substances per mL of aqueous solution for injection: 9.0-11 mg Chloroprocaine hydrochloride, 6-8 mg NaCl, and sufficient HCl to bring the pH to 3.0-4.0. We have found a method for obtaining the above-mentioned pharmaceutical composition, which comprises the following steps:

That is:
Mixing the required amounts of water for injection, chloroprocaine hydrochloride, NaCl and HCl in an inert gas atmosphere to give a medicated solution under inert gas;
Filtering the medicinal solution through a sterile filter (0.22 μm);
Dispensing the filtered medicinal solution into a vial under inert gas;
Sterilizing the filtered medicinal solution in a vial sealed under inert gas for at least 10 minutes (F ₀ > 10 min) at a temperature of at least 121 ° C. to obtain a sterile medicinal solution;
Have

  Chloroprocaine in the form of hydrochloride or 2- (diethylaminoethyl) -4-amino-chlorobenzoate (CAS: 3858-89-7) (chloroprocaine hydrochloride) has long been known for more than 50 years Anesthetic substance. Chloroprocaine (hydrochloride) has the same pharmaceutical characteristics as lidocaine, and has a short expression time (15 to 20 minutes) and a short duration (30 to 60 minutes) (Non-patent Document 3). Chloroprocaine is rapidly metabolized; in fact, it has a plasma half-life of 45-60 seconds, making it the most rapidly metabolized anesthetic in currently used clinics (non-patent literature). 4 and 5). Given this feature, chloroprocaine has very low systemic toxicity. Chloroprocaine is also used as a local anesthetic in outpatient surgery when very short anesthesia is required (3, 6).

  All of these apparent benefits, in particular the chloroprocaine hydrochloride, chloroprocaine, but the currently used formulation, “Chloroprone Hydroinjection, USP”, USP from Bedford Laboratories (Boehringer Ingelheim), USP, USP, The company Nesacine®-MPF is exclusive in the epidural but not in intrathecal applications and is endorsed by, for example, the FDA and Swiss Medicine. In this regard, for the purpose of eliminating the unintentional and accidental unauthorized use of these prescriptions, the relevant commercial information leaflet is illustratively advised for intrathecal use. Give a specific awakening. As a result, chloroprocaine hydrochloride is not currently used for intrathecal anesthesia, there is no suitable formulation, and it is not approved for this type of administration in the current market. Therefore, the object of the present invention is to solve the problems of the prior art and enable administration of chloroprocaine hydrochloride intrathecally by preferably providing a novel preparation applicable to this application example. This is because, with the exception of multiple attempts mentioned in the literature, all previously developed formulations have proved inappropriate to allow safe use of chloroprocaine hydrochloride intrathecally It is.

  Foldes and McNall found in clinical anesthesia (Non-Patent Document 7) Almost immediately after administration of chloroprocaine hydrochloride into the medullary cavity, it was hydrolyzed by endogenous cholinesterase very quickly. This route (that is, not actually undertaken in terms of not leading to the development of a specific formulation) was proposed at the time of so-called Nesacaine (registered trademark) -CE (Non-Patent Document 8). It was rapidly discontinued in terms of multiple incidental serious events of intrathecal administration during “normal” epidural administration of the preparations utilized. In particular, when in trouble, lower limb paralysis and sacral nerve dysfunction, which occurs when complete degradation is achieved in 6-12 weeks, in some cases, have been found permanently. In some subsequent studies, despite low pH and / or the presence of preservatives (sodium bisulfite) in Nesacaine®-CE has been implicated in diseases (Non-Patent Documents 9 and 10). In the mid-1990s, a new formulation containing Nesacaine (registered trademark) -MPF is currently available despite the fact that other preservatives such as EDTA were removed from the formulation marketed at that time (Non-patent Document 11). Despite unauthorized experiments performed (Non-Patent Documents 12, 13, 14 and 15), the overall picture is still unknown and other studies published at the same time (Non-Patent Document 16) Considers the use of modern formulations as it actually contributes to the strong neuroprotective properties, especially for bisulfite, and does not contain excipients Than is. Despite these further developments being discussed and disputed (Non-Patent Document 17), the current situation is that the formulation does not have an existing preservative (contains an antioxidant, sodium bisulfite). Are not yet approved for intrathecal use, and no special formulation has yet been developed for this type of dosage form. This is the state of current research that has proven to be inadequate and is being implemented, given previous experience and recent developments that contribute to the side effects of the presence of bisulfite and / or acidic environments. Therefore, chloroprocaine hydrochloride is still considered unsuitable for intrathecal administration in that the following matters are raised as a whole. This matter is as follows:

That all the neurotoxic diseases that occur are actually associated with a particularly problematic form of administration;
The pH of the commercial chloroprocaine hydrochloride solution is in each case distinguishably lower than that of other anesthetic solutions and may therefore be involved in the problems that arise.

  Since the above problems of the prior art employ a drug for intrathecal anesthesia, the present inventors have a solution having chloroprocaine hydrochloride in water for injection and have no preservative, particularly sodium bisulfite. It has surprisingly been found that by using the composition it can be solved. According to a particularly preferred embodiment, a pharmaceutical composition suitable for intrathecal administration is provided in the form of an aqueous solution, which consists of the following substances per mL of aqueous solution for injection: 9.0-11 mg of chloro Procaine hydrochloride, 6-8 mg NaCl, and a sufficient amount of HCl to bring the pH to 3.0-4.0.

  According to a particularly preferred embodiment, the components of the composition of the invention are equilibrated within the aforementioned parameters until an osmotic pressure of 270 to 300 mOsm / kg is achieved.

  According to another particularly preferred embodiment, the components of the composition of the invention are equilibrated within the aforementioned parameters until the relative density at 20 ° C. is between 1.0070 and 1.0080.

  Preferably, the novel pharmaceutical composition provided by the inventors is manufactured according to the novel method constructed by the inventors, which method comprises the following steps:

That is:
Mixing the required amounts of water for injection, chloroprocaine hydrochloride, NaCl and HCl in an inert gas atmosphere to give a medicated solution under inert gas;
Filtering the medicinal solution through a sterile filter (0.22 μm);
Dispensing the filtered medicinal solution into a vial under inert gas;
Sterilizing the filtered medicinal solution in a vial sealed under inert gas for at least 10 minutes (F ₀ > 10 min) at a temperature of at least 121 ° C. to obtain a sterile medicinal solution;
Have

  Preferably, the inert gas is selected from the group consisting of nitrogen and noble gases. The step of purging with inert gas is particularly important and must ensure the lowest possible oxygen remaining for the purpose of keeping the active body stable for long periods (less than 5 years under normal storage conditions). I must. Preferably dispensed into 5 mL vials. The vial may be made of clear glass in view of the high stability of certain solutions provided by the present invention. In addition to being able to exclude preservatives such as antioxidants in particular, the methods constructed by the inventors are not aseptic in terms of sterilization (aseptic production currently used in prior art compositions). More effective results can be achieved than can be achieved by filtration).

  As mentioned above, nitrogen is applied to the medicinal solution during all of the manufacturing steps from degassing water for injection to sealing the vial. In conclusion, the present invention makes it possible to use a composition containing chloroprocaine hydrochloride as a solution in water for injection and no preservative for the manufacture of a drug for intrathecal anesthesia. Have been shown to solve the above problems.

Claims (19)

  Use of a composition having a solution of chloroprocaine hydrochloride in water for injection and no preservative for the preparation of a drug for intrathecal anesthesia.   The use according to claim 1, characterized in that the composition has a pH of 3.0 to 4.0.   Use according to claim 1 or 2, characterized in that the composition consists of chloroprocaine hydrochloride, sodium chloride, water for injection and hydrochloric acid.   The composition is composed of 9 to 11 mg of chloroprocaine hydrochloride, 6 to 8 mg of NaCl, and a sufficient amount of HCl to adjust the pH to 3.0 to 4.0 per 1 mL of an aqueous solution for injection. Use according to claim 2 or 3.   Use according to claim 4, characterized in that the composition has an osmotic pressure of 270 to 300 mOsm / kg.   Use according to claim 4 or 5, characterized in that the composition has a relative density at 20 ° C of 1.0070 to 1.0080. A method for producing a drug intended for intrathecal anesthesia,
A method comprising using a composition having a solution of chloroprocaine hydrochloride in water for injection and having no preservative.   The method of claim 7, wherein the composition has a pH of 3.0 to 4.0.   The method according to claim 7 or 8, wherein the composition comprises chloroprocaine hydrochloride, sodium chloride, water for injection and hydrochloric acid.   The composition is composed of 9 to 11 mg of chloroprocaine hydrochloride, 6 to 8 mg of NaCl, and a sufficient amount of HCl to adjust the pH to 3.0 to 4.0 per 1 mL of an aqueous solution for injection. The method according to claim 8 or 9.   The method of claim 10, wherein the composition has an osmotic pressure of 270 to 300 mOsm / kg.   The method according to claim 10 or 11, wherein the composition has a relative density of 1.0070 to 1.0080 at 20 ° C. Per mL of aqueous solution for injection:
9.0-11 mg of chloroprocaine hydrochloride;
6-8 mg NaCl; and a sufficient amount of HCl to bring the pH to 3.0-4.0;
A pharmaceutical composition characterized by being in the form of an aqueous solution.   The pharmaceutical composition according to claim 13, wherein the composition has an osmotic pressure of 270 to 300 mOsm / kg.   The pharmaceutical composition according to claim 13 or 14, wherein the composition has a relative density of 1.0070 to 1.0080 at 20 ° C. A method of obtaining a pharmaceutical composition according to any one of claims 13 to 15, comprising:
Mixing the required amounts of water for injection, chloroprocaine hydrochloride, NaCl and HCl in an inert gas atmosphere to give a medicinal solution under inert gas;
Filtering the medicinal solution through a sterile filter (0.22 μm);
Dispensing the filtered medicinal solution into a vial under inert gas;
Sterilizing the filtered medicinal solution in a vial sealed under inert gas for at least 10 minutes (F ₀ > 10 min) at a temperature of at least 121 ° C. to obtain a sterile medicinal solution;
A method characterized by comprising:   The method of claim 16, wherein the inert gas is selected from the group consisting of nitrogen and a noble gas.   The method according to claim 16 or 17, wherein the dispensing is performed in a 5 mL vial.   19. The method of claim 18, wherein the vial is a dark glass or clear glass vial that protects the contents from light.